Drug and transmitter interactions in cerebral cortex and the extrapyramidal system in experimental animals as well as in man may be altered with senescence. Such alterations may be contributory to loss of cerebral function with aging, senile dementia and the progressive course of extrapyramidal disease. With senescence there are found selective decrements in the dopamine-stimulated component of adenylate cyclase activity in caudate nucleus of both rat and rabbit and in the stimulations by both histamine and dopamine of activity in hypothalamus and cortical regions. Spiroperidol binding sites in rabbit striatum and cortical regions are decreased as well. Studies will be carried out to elucidate as a function of age in rat and rabbit: (1) alterations in dopaminergic neurons, particularly the post-synaptic component in the basal ganglia; (2) alterations in responsiveness to drugs which interact with aminergic transmitter systems; (3) changes in cortical catecholamine and other aminergic receptor adenylate cyclase systems, including drug interactions and in the rat; (4) the extent and nature of biochemical and behavioral compensation to denervation of dopaminergic and/or related transmitter systems in the nigrostriatal system and changes in cortical receptor-adenylate cyclase systems following destruction of catecholamine neuronal input to cortex. Included will be evaluation of the mechanisms for changes in adenylate cyclase and receptor binding sites. Possible age-related changes in extent and propensity for receptor desensitization and in receptor supersensitivity will be evaluated, as will be other related aspects of plasticity of central aminergic systems. These studies provide an approach for elucidating the nature and functional significance of changes with age in specific components of aminergic receptor systems. This investigation would provide insight into the nature and possible treatment of brain dysfunction due to senescence.